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7 results on '"Alexander, Thomas B"'

1. Safety, pharmacokinetics, and pharmacodynamics of panobinostat in children, adolescents, and young adults with relapsed acute myeloid leukemia.

Author

Karol, Seth E, Karol, Seth E, Cooper, Todd M, Mead, Paul E, Crews, Kristine R, Panetta, John C, Alexander, Thomas B, Taub, Jeffrey W, Lacayo, Norman J, Heym, Kenneth M, Kuo, Dennis J, Schiff, Deborah E, Bhojwani, Deepa, Ge, Yubin, Klco, Jeffery M, Ribeiro, Raul C, Inaba, Hiroto, Pui, Ching-Hon, Rubnitz, Jeffrey E, Karol, Seth E, Karol, Seth E, Cooper, Todd M, Mead, Paul E, Crews, Kristine R, Panetta, John C, Alexander, Thomas B, Taub, Jeffrey W, Lacayo, Norman J, Heym, Kenneth M, Kuo, Dennis J, Schiff, Deborah E, Bhojwani, Deepa, Ge, Yubin, Klco, Jeffery M, Ribeiro, Raul C, Inaba, Hiroto, Pui, Ching-Hon, and Rubnitz, Jeffrey E

Abstract

BackgroundNovel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML).MethodsTo determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m2 ) before and in combination with fludarabine and cytarabine.ResultsAll dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status.ConclusionsPanobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.

Published
2020

2. Genomic subtyping and therapeutic targeting of acute erythroleukemia.

Author

Iacobucci, Ilaria, Iacobucci, Ilaria, Wen, Ji, Meggendorfer, Manja, Choi, John K, Shi, Lei, Pounds, Stanley B, Carmichael, Catherine L, Masih, Katherine E, Morris, Sarah M, Lindsley, R Coleman, Janke, Laura J, Alexander, Thomas B, Song, Guangchun, Qu, Chunxu, Li, Yongjin, Payne-Turner, Debbie, Tomizawa, Daisuke, Kiyokawa, Nobutaka, Valentine, Marcus, Valentine, Virginia, Basso, Giuseppe, Locatelli, Franco, Enemark, Eric J, Kham, Shirley KY, Yeoh, Allen EJ, Ma, Xiaotu, Zhou, Xin, Sioson, Edgar, Rusch, Michael, Ries, Rhonda E, Stieglitz, Elliot, Hunger, Stephen P, Wei, Andrew H, To, L Bik, Lewis, Ian D, D'Andrea, Richard J, Kile, Benjamin T, Brown, Anna L, Scott, Hamish S, Hahn, Christopher N, Marlton, Paula, Pei, Deqing, Cheng, Cheng, Loh, Mignon L, Ebert, Benjamin L, Meshinchi, Soheil, Haferlach, Torsten, Mullighan, Charles G, Iacobucci, Ilaria, Iacobucci, Ilaria, Wen, Ji, Meggendorfer, Manja, Choi, John K, Shi, Lei, Pounds, Stanley B, Carmichael, Catherine L, Masih, Katherine E, Morris, Sarah M, Lindsley, R Coleman, Janke, Laura J, Alexander, Thomas B, Song, Guangchun, Qu, Chunxu, Li, Yongjin, Payne-Turner, Debbie, Tomizawa, Daisuke, Kiyokawa, Nobutaka, Valentine, Marcus, Valentine, Virginia, Basso, Giuseppe, Locatelli, Franco, Enemark, Eric J, Kham, Shirley KY, Yeoh, Allen EJ, Ma, Xiaotu, Zhou, Xin, Sioson, Edgar, Rusch, Michael, Ries, Rhonda E, Stieglitz, Elliot, Hunger, Stephen P, Wei, Andrew H, To, L Bik, Lewis, Ian D, D'Andrea, Richard J, Kile, Benjamin T, Brown, Anna L, Scott, Hamish S, Hahn, Christopher N, Marlton, Paula, Pei, Deqing, Cheng, Cheng, Loh, Mignon L, Ebert, Benjamin L, Meshinchi, Soheil, Haferlach, Torsten, and Mullighan, Charles G

Abstract

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.

Published
2019

3. International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia

Author

Hrusak, Ondrej, de Haas, Valerie, Stancikova, Jitka, Vakrmanova, Barbora, Janotova, Iveta, Mejstrikova, Ester, Capek, Vaclav, Trka, Jan, Zaliova, Marketa, Luks, Ales, Bleckmann, Kirsten, Möricke, Anja, Irving, Julie, Konatkowska, Benigna, Alexander, Thomas B, Inaba, Hiroto, Schmiegelow, Kjeld, Stokley, Simone, Zemanova, Zuzana, Moorman, Anthony V, Rossi, Jorge Gabriel, Felice, Maria Sara, Dalla-Pozza, Luciano, Morales, Jessa, Dworzak, Michael, Buldini, Barbara, Basso, Giuseppe, Campbell, Myriam, Cabrera, Maria Elena, Marinov, Neda, Elitzur, Sarah, Izraeli, Shai, Luria, Drorit, Feuerstein, Tamar, Kolenova, Alexandra, Svec, Peter, Kreminska, Olena, Rabin, Karen R, Polychronopoulou, Sophia, da Costa, Elaine, Marquart, Hanne Vibeke, Kattamis, Antonis, Ratei, Richard, Reinhardt, Dirk, Choi, John K, Schrappe, Martin, Stary, Jan, Hrusak, Ondrej, de Haas, Valerie, Stancikova, Jitka, Vakrmanova, Barbora, Janotova, Iveta, Mejstrikova, Ester, Capek, Vaclav, Trka, Jan, Zaliova, Marketa, Luks, Ales, Bleckmann, Kirsten, Möricke, Anja, Irving, Julie, Konatkowska, Benigna, Alexander, Thomas B, Inaba, Hiroto, Schmiegelow, Kjeld, Stokley, Simone, Zemanova, Zuzana, Moorman, Anthony V, Rossi, Jorge Gabriel, Felice, Maria Sara, Dalla-Pozza, Luciano, Morales, Jessa, Dworzak, Michael, Buldini, Barbara, Basso, Giuseppe, Campbell, Myriam, Cabrera, Maria Elena, Marinov, Neda, Elitzur, Sarah, Izraeli, Shai, Luria, Drorit, Feuerstein, Tamar, Kolenova, Alexandra, Svec, Peter, Kreminska, Olena, Rabin, Karen R, Polychronopoulou, Sophia, da Costa, Elaine, Marquart, Hanne Vibeke, Kattamis, Antonis, Ratei, Richard, Reinhardt, Dirk, Choi, John K, Schrappe, Martin, and Stary, Jan

Abstract

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+ leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19- and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial.

Published
2018

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